Foot complications of diabetes adversely affect public health. Estimated lifetime risk of foot ulcers in diabetic patients is 25%;ulcers cause most of the 80,000 lower-extremity amputations in U.S. diabetic patients annually. Health-care costs total $11 billion per year, with minorities disproportionately affected. Skin ulceration in neuropathic diabetic feet arises from mechanical contact between the foot and shoe that such patients cannot feel. Unsurprisingly, the foot-shoe interface is a prime focus of study. However, design of therapeutic footwear for diabetic patients remains based on anecdote;pedorthists'skills are rarely informed by scientific data. We propose to build on our successfully applied finite element (FE) method to foot biomechanics (grant 5R01 HD037433). We will provide guidance for designing therapeutic insoles and explore techniques for patient-specific modeling. In Specific Aim 1, using 3D patient-specific FE models, we will define general principles for insole design to ensure plantar pressure relief in different foot types of those without significant deformity or abnormal focal pressure. To simulate structure/function, our novel optimization technique will help define a "loading state" for the model, allowing configuration change. In the validation phase, we will directly compare measured with predicted plantar pressures in flat vs. conforming insoles, multi-layers vs. single layers, varying insole thicknesses, and differing insole material properties available for primary prevention. In Specific Aim 2, we will examine the feasibility of modeling at-risk feet with single or multiple regions of elevated plantar pressure based on pressure measurements. We will develop patient-specific models obtained by "morphing" the FE meshes from Specific Aim 1, based on anthropometric data and tissue-thickness measurements derived from ultrasound. In Specific Aim 3, we will use models of multi-featured therapeutic insoles for at-risk feet (e.g., metatarsal pads, bars, altered arch supports, and variations in material depth under individual MTHs) that will be validated using in-shoe pressure1 measurements. These experiments and simulations should lead to (a) a set of general rules for therapeutic insole design and (b) a tool for patient-specific modeling in complex cases. If lower-extremity ulcers can be prevented before they lead to amputation, the U.S. will realize substantial cost savings in terms of patient quality of life and less need for lengthy rehabilitation, with its associated mental and physical suffering.